Tamoxifen is an antiestrogen drug widely utilized for the adjuvant hormonal treatment of breast carcinoma. Its use in the primary prophylaxis of this disease is currently being proposed. Although the drug has few side effects, its precise action on breast tissue that has not undergone neoplastic transformation has not been fully elucidated. This prospective, randomized study assessed the estrogen activity of tamoxifen on the mammary gland epithelium of premenopausal patients using a quantitative analysis of mammary epithelium lysosome identified by the cytochemical technique of GOMORI for acid phosphatase and by light microscopy. Tamoxifen significantly increased the number of lysosomes only during the secretory phase of the menstrual cycle. We concluded that the early effect of the drug on normal mammary tissue is synergistic with the effect of estrogen during the premenopausal period.

Intensification of post-remission therapy improves the cure rate of acute myeloid leukemia (AML) but is often accompanied by unacceptable toxicity. From 1985 to 1992 the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial to evaluate the effectiveness of one single postremission course of high-dose cytarabine (HDAC) in terms of leukaemia-free and overall survival in adults with de novo AML.

The aim of the study was to verify whether the combination of an antiserotoninergic, metoclopramide, and a steroid could improve the complete control (CC) of delayed emesis, a contraversial issue, 105 patients undergoing highly-emetogenic chemotherapy, receiving Ondansetron (O) 8 mg + Dexamethasone 20 mg i.v. for the prevention of acute emesis, were randomly treated p.o for three further days with a) Metoclopramide 10 mg x 3 b) the same as a) + Methylprednisolone 4 mg c) the same as b) + O 8 mg x 3. CC (acute+delayed emesis) over three cycles was: a) 0.b) 12.5%, c) 38.5% (p = 0.02). Days with nausea/vomiting: 59%, 51%, 29.7% of the total observed period, respectively (b vs c p = 0.0000). CC of acute emesis was similar in the first cycle (about 85%), remained unchanged in the following cycles (c) and decreased to 30% and 68% in the third cycle (a and b) (p = 0.01). The three drug combination significantly improved complete control of acute and delayed emesis over successive chemotherapy cycles.

A randomized trial was carried out to investigate the effect of 12 months administration of the gonadotrophin-releasing hormone agonist (GnRHa) Zoladex in combination with either placebo or medroxyprogesterone acetate (MPA) from the third month. Bone density, markers of bone resorption, symptoms and uterine volume were monitored in 24 women with symptomatic fibroids or menstrual problems. A total of 21 women were recruited to act as controls for the assessment of bone parameters. Vasomotor side-effects were reduced significantly in the MPA-treated group. The reduction in uterine volume in women with fibroids was not impaired by the addition of MPA. The bone markers osteocalcin and alkaline phosphatase were assessed in plasma, and the cross-links pyridinoline and deoxypyridinoline measured in urine. Changes in these markers are reported which suggest increases in bone resorption during the period of observation. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry at the spine and forearm. The net reduction in BMD at the spine in the treated groups was 4.30 +/- 0.59% at 6 months and 7.50 +/- 0.78% at 1 year, with no change in the control group. No change was seen in forearm BMD. No protective effect was observed when MPA was added. At 1 year after the completion of treatment, BMD remained significantly below baseline, and this has implications for the prolonged use of GnRHa.

The efficacy and tolerability of granisetron in the management of acute and delayed emesis was compared with that of a multiple antiemetic drug combination regimen, including metoclopramide, dexamethasone, lorazepam and orphenadrine. The trial was a randomized, cross-over study involving 111 patients with gynecological cancers undergoing chemotherapy with cisplatin. Granisetron was significantly more effective than the combination regimen during the first 24 h after chemotherapy; complete response, rates were 67 and 48%, respectively (p = 0.002). There was a significant reduction in the effectiveness of the combination during the second treatment cycle, compared with the first. In contrast, the efficacy of granisetron did not differ between the two cycles. The response rate during the 6 days after chemotherapy was 40.8% in both groups. At the end of the study, 55% of patients preferred granisetron and 23% preferred the combination (p < 0.001). Granisetron was well tolerated. The principal adverse event was headache, which was reported in 7% of patients. The results of this study confirm that granisetron is effective in the treatment of cisplatin-induced nausea and vomiting during the 24 h after chemotherapy.

To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure.

Experimental data have suggested that the pineal hormone melatonin (MLT) may counteract chemotherapy-induced myelosuppression and immunosuppression. In addition, MLT has been shown to inhibit the production of free radicals, which play a part in mediating the toxicity of chemotherapy. A study was therefore performed in an attempt to evaluate the influence of MLT on chemotherapy toxicity. The study involved 80 patients with metastatic solid tumors who were in poor clinical condition (lung cancer: 35; breast cancer: 31; gastrointestinal tract tumors: 14). Lung cancer patients were treated with cisplatin and etoposide, breast cancer patients with mitoxantrone, and gastrointestinal tract tumor patients with 5-fluorouracil plus folates. Patients were randomised to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day p.o. in the evening). Thrombocytopenia was significantly less frequent in patients concomitantly treated with MLT. Malaise and asthenia were also significantly less frequent in patients receiving MLT. Finally, stomatitis and neuropathy were less frequent in the MLT group, albeit without statistically significant differences. Alopecia and vomiting were not influenced by MLT. This pilot study seems to suggest that the concomitant administration of the pineal hormone MLT during chemotherapy may prevent some chemotherapy-induced side-effects, particularly myelosuppression and neuropathy. Evaluation of the impact of MLT on chemotherapy efficacy will be the aim of future clinical investigations.

Stomatitis is a major dose-limiting toxicity of bolus fluorouracil (5FU)-based chemotherapy regimens, despite the use of oral cryotherapy. Pursuant to preliminary data that suggested a sucralfate oral solution could alleviate chemotherapy-induced oral mucositis, we developed a prospective trial to test this contention.

To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b.

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

Twenty-three patients with metastatic colorectal carcinoma were randomized as part of two multicenter Phase III trials to receive either 5-fluorouracil (5-FU)/interferon alpha-2A (INF-alpha) or 5-FU +/- leucovorin. The patients were evaluated regularly for response by CT of the abdomen when treatment began and then every six to eight weeks. incidentally, we found that four of 13 patients treated with 5-FU/INF-alpha and none of ten patients treated with 5-FU +/- leucovorin developed hepatic steatosis during treatment. The diagnoses were based on a decreased CT value of the liver parenchyma by the repeated CT, and histologically verified by liver biopsies. There was no relationship to cumulative 5-FU or INF-alpha dose. Based on posttreatment CT, the liver parenchyma changes were reversible after therapy was stopped. Recognition of this condition in patients receiving 5FU/INF-alpha is important to prevent a patient from being labeled as having progressive hepatic metastases.

Ifosfamide is one of the most efficient antimitotic in soft tissue sarcoma. To try to find a possible dose-effect, 10 patients with advanced pretraited relapsed soft tissue sarcoma received 15 g/m2/cycle ifosfamide in continuous infusion during 5 days. A pharmacokinetic study was done for 2 patients. All patients received growth factors, ondansetron and 8 clonazepam. Renal toxicity was evaluated after the first and the second cycle. Twenty two cycles were delivered to patients who have been already treated with ifosfamid (10 patients with 15 g/m2 to 54 g/m2, median 27 g/m2) or cis platinum (2 patients). No major renal or neurologic toxicity was observed; only subclinical modifications of urinary enzymes excretion were found. Two patients had visual hallucinations at the end of a cycle and just in the 2 following days; another presented a neuropathy of inferior limbs. Hematological toxicity was very limited. Pharmacokinetic study did not show induction mechanism at this dosage and with this type of administration. So ifosfamide 3 g/m2 during 5 days is feasible. The few level of complications observed is perhaps linked to the daily dose of 3 g/m2 instead of 4 g/m2 or more used in the other studies.

To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM).

Dysplasia of the uterine cervix is a recognized precancerous condition. Because of the observed ability of retinoids to suppress various cell lines in vitro, a number of clinical studies have examined the effect these agents have on cervical dysplasia, with the object of developing a means of chemoprevention of cervical malignancies in women at risk. Three cervical cancer chemoprevention trials with Retinamide II (RII) have been conducted at the Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China. A pilot study used RII to intervene in cases of precancerous cervical dysplasia. Twenty-seven women with mild, moderate, or severe cervical dysplasia, pathologically confirmed, were treated by RII suppositories, 10 mg QD, given intravaginally for 6 months (each course lasting 3 months). The results indicated that after the second course, the overall response rate was 96.29% and the complete response rate was 88.89%. In general, side effects were mild. A little cervical and vaginal irritation was well tolerated. In the second double-blind study, patients with precancerous cervical lesions were randomized into two groups, one treated with RII suppository intravaginally and the other with a placebo, once daily for 50 days in two courses. Precancerous lesions in 68.76% of patients in the treatment arm disappeared, with an overall effective rate of 74.29% after two courses of treatment with RII. Its curative effect was approximately that of laser beam radiation and electrocautery (P > 0.05), and differed significantly (P < 0.01) from that of traditional antiinflammatories. RII can be a major measure in prevention and treatment of cervical cancer in high-incidence areas in China. In the third trial, we are conducting a randomized double-blind study placebo controlled, in a high-incidence area of cervical cancer (Xiang-Yuan county, Shang Xi Province, China). At present, the patients are being followed up and the study will be completed after 2 years.

In order to study the short-to medium-term effects of cytotoxic chemotherapy (CT) for acute lymphoblastic leukaemia (ALL) on growth in prepubertal children, a prospective study of weight (Wt), height (Ht), sitting height (SH) and body mass index (BMI) was performed in 31 children receiving intensive CT for ALL. Two pubertal children, 1 child with Down's syndrome and 3 children who had cranial irradiation were excluded from the analysis. Monthly measurements were presented as change in standard deviation scores from baseline (delta SDS). The median age at diagnosis was 4.4 years (range, 1.1-14). The median duration of study per subject was 18 months (3-24). The median delta SDS-Ht reached a nadir of -0.35 at 6 months after the start of CT (p = 0.001, Wilcoxon signed rank test); the median delta SDS-SH was -0.55 at 3 months (p = 0.02); the median delta SDS-Wt and delta SDS-BMI increased at 2 months to 0.15 (p = 0.03) and 0.5 (p = 0.002), respectively. The median delta SDS-BMI was also elevated at 10 months (0.75, p = 0.01) reflecting the relative delay in recovery of Ht-SDS in comparison to Wt-SDS. The median SH:Ht ratio, a measure of disproportion, was reduced at 3 months (delta SH:Ht ratio, -0.01, p = 0.009). No significant changes in Ht-SDS, BMI-SDS or SH:Ht from baseline were evident at the end of the CT. Cytotoxic CT for ALL in childhood has a significant adverse effect on growth, but there is some evidence for recovery before the end of CT.

Forty patients with previously untreated epithelial ovarian cancer (OC), with FIGO stages Ic-IV, were randomly allocated to receive intravenously either carboplatin (C) 400 mg/m2 every three weeks (C arm, 20 patients) or a combination of C 350 mg/m2, ifosfamide (I) 5 g/m2 with mesna every three weeks, vincristine (V) 1.4 mg/m2 (maximum total dose 2 mg) and bleomycin (B) 30 mg every ten days (CIVB arm, 20 patients). Responding patients received 6 courses of chemotherapy and all 40 patients were evaluable for toxicity, response and survival. Clinical characteristics of patients were similar in both arms. Clinico-imaging results with chemotherapy were as follows: in C arm, clinical complete remission (cCR) 11 (55%) and partial remission (cPR) five (25%) patients for an overall response rate (ORR) 80%. For CIVB arm, cCR ten (50%) and cPR four (20%) patients for an ORR 70%. Second look operation (SLO) was performed in three of the 11 cCR patients in the C arm and six of the ten cCR patients in the CIVB arm. Pathological CR (pCR) was confirmed in two of the three cCR C arm patients and two of the six in the CIVB patients. In the first interim analysis statistically significant differences, all favoring monochemotherapy, were seen in response duration, time to progression, disease-free and overall survival. These results along with the severe myelotoxicity resulting in dose reductions in the CIVB patients led us to stop enrolling new patients and follow this population closely for long-term results. These confirmed the first observations of the superiority of single-agent carboplatin in response duration (p = 0.034), time to progression (p = 0.028), disease-free survival (p = 0.010) and overall survival (p = 0.043). Because of the above reasons we have concluded that monochemotherapy with carboplatin is to be preferred over carboplatin in combination with other drugs.

Porfiromycin (methyl mitomycin C) has been shown in laboratory studies to have increased preferential cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy (RT). The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with RT in the management of squamous cell carcinoma of the head and neck. Between October 1989 and July 1992, 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to RT. Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means. Patients were treated with standard fractionated daily RT to a total median dose of 63 Gy, with porfiromycin administered on days 5 and 47 of the course of RT. Upon completion of this phase I trial, a phase III trial was initiated in November 1992 randomizing patients with squamous cell carcinoma of the head and neck to RT with mitomycin C vs. RT with porfiromycin. There is no radiation only arm in this current trial. To date, 75 patients have been entered on this trial and acute toxicity data are available on 67 patients (34 porfiromycin, 31 mitomycin C) who have completed their entire course of treatment. Median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months. Of the 21 patients, 5 were treated at a dose of 50 mg/M2, 4 at 45 mg/M2, and the final 12 at 40 mg/M2, which appeared to result in acceptable acute hematological and nonhematological toxicities. As of December 1995, 14 of the 21 patients have died with disease and 7 remain alive and free of disease, resulting in a 5-year actuarial survival of 32%. Of the patients enrolled to date in the phase III randomized trial of mitomycin C vs. porfiromycin, there have been no statistically significant differences between the two arms with respect to white blood cell count (WBC), platelet, or hemoglobin nadirs. Acute nonhematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial died during treatment, apparently of nondrug-related causes. We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year no evidence of disease survival rate of 32% in patients with locally advanced disease and a low probability of cure, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years. Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted.

Results of cytotoxic chemotherapy for hormone-resistant prostate cancer are not impressive. One of the substances which seems to have a therapeutic benefit is 5-fluorouracil (5-FU). The effect of 5-FU can be modulated by addition of folinic acid (FA). We tested in a prospective, randomized phase II trial monotherapy with 5-FU versus the combination of 5-FU and high-dose FA.